Substituted pyrazoles

• US 20060264419A1
• Filed: 03/08/2004
• Published: 11/23/2006
• Est. Priority Date: 04/05/2003
• Status: Abandoned Application

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Schiemann, Kai, Seyfried, Christoph, Schadt, Oliver, Finsinger, Dirk, Bartoszyk, Gerd, Van Amsterdam, Christoph, Ackermann, Karl-August, Arlt, Michael
• Application Number:
  US10/552,065
• Publication Number:
  US 20060264419A1
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/06 : Oxygen atoms
• CPC Class Codes: C07D 453/06 : containing isoquinuclidine ring systems
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 491/08 : Bridged systems

Abstract

The compounds of the formula (I) and salts and solvates thereof, in which X, R¹, R², R³, R⁴ and R⁵ have the meanings indicated in Claim (1), are suitable as ligands of 5 HT receptors.

Claims

1. Use of the compounds of the formula I

in which

X denotes CH or N,

R¹ denotes H, A, Hal, (CF₂)_nHet, (CH₂)_nAr, cycloalkyl having 3 to 7 C atoms, CF₃, NO₂, CN, C(NH)NOH or OCF₃,

R² denotes (CH₂)_nHet, (CH₂)_nAr, cycloalkyl having 3 to 7 C atoms or CF₃,

R³, R⁴ denote H, (CH₂)_nCO₂R⁵, (CH₂)_nCOHet, (CH₂)_nCON(R⁵)₂, (CH₂)_n000(CH₂)_nHet, CHO, (CH₂)_nOR⁵, (CH₂)_nHet, (CH₂)_nN(R⁵)₂, CH═

N—

OA, CH₂CH═

N—

OA, (CH₂)_nNHOA, (CH₂)_nN(R⁵)Het, (CH₂)_nCH═

N-Het, (CH₂)_n000R⁵, (CH₂)_nN(R⁵)CH₂CH₂OR⁵, (CH₂)_nN(R⁵)CH₂CH₂OCF₃, (CH₂)_nN(R⁵)C(R⁵)H000R⁵, (CH₂)_nN(R⁵)CH₂COHet, (CH₂)_nN(R⁵)CH₂Het, (CH₂)_nN(R⁵)CH₂CH₂Het, (CH₂)_nN(R⁵)CH₂CH₂N(R⁵)CH₂000R⁵, (CH₂)_nN(R⁵)CH₂CH₂OR⁵, (CH2)_nN(R⁵)CH2CH₂N(R⁵)₂, CH═

CH000R⁵, CH═

CHCH₂NR⁵Het, CH═

CHCH₂N(R⁵)₂, CH═

CHCH₂0R⁵, CH═

CHCH₂Het, (CH₂)_nN(R⁵)Ar, (CH₂)_nN(000R)COOR⁵, (CH₂)_nN(CONH₂)000R⁵, (CH₂)_nN(CONH₂)CONH₂, (CH₂)_nN(CH₂000R)COOR⁵, (CH₂)_nN(CH₂CONH₂)000R⁵, (CH₂)_nN(CH₂CONH₂)CONH₂, (CH₂)_nCHR⁵COR⁵, (CH₂)_nCHR⁵000R⁵,

(CH₂)_nCHR⁵CH20R⁵, where in each case one of the radicals R³ or R⁴ has the meaning H,

R⁵ denotes H or A

A denotes straight-chain or branched alkyl or cycloalkyl having 2 to 4 C atoms, having 1 to 10 C atoms, alkenyl having 2 to 10 C atoms, alkoxyalkyl having 2 to 10 C atoms or cycloalkyl having 4 to 7 C atoms, each of which is unsubstituted or substituted by Hal or CN,

Het preferably denotes a saturated, unsaturated or aromatic mono or bicyclic heterocyclic radical having 1 to 15 C atoms which is unsubstituted or mono- or polysubstituted by A and/or Hal or a linear radical having 1 to 15 C atoms containing one or two hetero atoms,

Ar denotes a phenyl radical which is unsubstituted or mono or polysubstituted by A and/or Hal, ORt, OOCR⁵, COORS, CON(R⁵)₂, CN, NO₂, NH₂, NHCOR⁵, CF₃ or SO2CH₃,

n denotes 0, 1, 2, 3, 4 or 5 and

Hal denotes F, Cl, Br or I,

and salts and solvates, enantiomers and racemates thereof for the preparation of a medicament for the treatment and prophylaxis of diseases which can be influenced by the binding of the compounds of the formula I to 5 HT receptors.

2. Use of compounds according to claim 1 and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament having a 5-HT receptor-antagonistic action.

3. Use of compounds according to claim 1 and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament having a 5-HT_2A receptor-antagonistic action.

4. Use of compounds of the formula I according to claim 1, and/or physiologically acceptable salts or solvates thereof for the preparation of a medicament for the prophylaxis and/or treatment of psychoses, neurological disorders, amyotrophic lateral sclerosis, eating disorders, such as bulimia, anorexia nervosa, of premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

5. Use of the compounds of the formula I according to claim 1, in which R¹ denotes phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6, 3,4, 3,5- or 3,6-difluoro-, dichloro- or dicyanophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxy- or triethoxyphenyl, thiophen 2-yl or thiophen-3-yl or 1-, 2- or 3-pyrrolyl.

6. Use of the compounds of the formula I according to claim 1, in which R³ denotes (CH2)_nCO₂R⁵, (CH2)_nCO-Het, CHO, CH₂OR⁵, (CH2)_n-Het, (CH2)_nN(R⁵)₂ or CH═

N—

OA, (CH₂)_nN(R⁵)Het, (CH2)_nN(R⁵)CH₂CH₂OR⁵, (CH2)_nN(R⁵)CH₂Het, (CH2)_nN(R⁵)CH2CH2Het, (CH2)nN(R⁵)CH2CH2N(R⁵)2, CH═

CHCH₂NR⁵Het, CH═

CHCH2N(R⁵)₂, CH═

CHCH₂OR⁵, CH═

CHCH₂Het or (CH2)_nN(R⁵)Ar.

7. Use of the compounds of the formula I according to claim 1, in which R⁴ denotes H.

8. Use of the compounds of the formula I according to claim 1, in which R² denotes phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-difluoro- or dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl, 2- or 3-furyl.

9. Use of the compounds of the formula I according to claim 1, in which X has the meaning CH.

10. Use of the compounds of the formula (a) to (o) according to claim 1:

[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-ylmethyl]-(4-methylpiperazin-1-yl)amine 

 

(a)
4-{2-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl]-ethyl}morpholine 

 

(b)
4-{3-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl]allyl}morpholine 

 

(c)
1-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl-methyl]pyrrolidin-3-ol 

 

(d)
1-[1-(4′

-fluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1H-pyrazol-4-ylmethyl]-4-methylpiperazine 

 

(e)
1-[5-(2-fluorophenyl)-1-(4-thiophen-3-ylphenyl)-1H-pyrazol-4-ylmethyl]-4-methylpiperazine 

 

(f)
1-[5-furan-2-yl-1-(4-thiophen-3-ylphenyl)-1H-pyrazol-4-yl-methyl]-4-methylpiperazine 

 

(g)
N¹-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl-methyl]ethane-1,2-diamine 

 

(h)
2-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl-methyl]amino}ethanol 

 

(i)
[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-ylmethyl]-(2-methoxyethyl)amine 

 

0)
2-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl-methyl]methylamino}ethanol 

 

(k)
1-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl-methyl]-4-methyl-[1,4]diazepam 

 

(l)
1-[1-(4′

-fluorobiphenyl-4-yl)-5-phenyl-1H-pyrazol-4-yl-methyl]-4-methylpiperazine 

 

(m)
1-[5-(2-fluorophenyl)-1-(4-pyrrol-1-ylphenyl)-1H-pyrazol-4-ylmethyl]-4-methylpiperazine 

 

(n)
[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-ylmethyl]-methyl-(1-methylpyrrolidin-3-yl)amine 

 

(o)

and salts and solvates thereof.